With the aging of society, there is an ongoing increase in the number of people suffering from demential diseases. Demential diseases can be induced by an enormous variety of etiologies. It is therefore very difficult to make an exact differential diagnosis of such a disease, and no therapy has been established for many demential diseases. Among demential diseases, normal pressure hydrocephalus (hereinafter referred to as NPH) including symptomatic normal pressure hydrocephalus following subarachnoid hemorrhage or cerebral meningitis and idiopathic normal pressure hydrocephalus of unknown cause is known to be dramatically improved by surgery (e.g. ventriculoperitoneal shunt). However, there can be little expectation that surgery will have any effect in improving symptoms of demential diseases found in elderly people, such as Alzheimer's disease, Parkinson's disease and cerebrovascular dementia, or the symptoms of diffuse brain injury, characterized by cerebral atrophy and ventricular enlargement. Thus, it is important to be able to differentiate at an early stage between NPH, which is treatable by surgery, and dementia for which surgical treatment is not effective. However, it is difficult to make such differentiation.
A classic diagnostic method for determing suitability for surgery involves continuously measuring a cerebrospinal pressure for a period of one day via drainage from lumbar vertebra to cerebrospinal cavity, to thereby monitor a pressure wave of cerebrospinal fluid (Symon, L., Dorsh, N. W. C., J. Neurosurg., 42: 258-273, 1975). However, this method is often clinically difficult because it requires a patient to be treated at rest in a bed in a clean environment, using appropriate instruments for continuous measurement and analysis and the like. Another method involves daily drainage of 40-50 ml of cerebrospinal fluid to assess improvements in symptoms, but this lacks reliability and carries a risk of complication such as infection of a site subjected to repeated puncture. A method for differentiating between atrophic Alzheimer-type senile dementia and NPH by assaying amyloid-related protein (α1-antichymotrypsin) in cerebral venous blood has been reported, but is not widely used because it requires invasive collection of cerebral venous blood and lacks effectiveness.
The rationale for monitoring a dynamic state of spinal fluid resides in the pathophysiology of these diseases. However, it is to be noted that measurement of a pressure wave of spinal fluid has been recently replaced by methods made possible by remarkable advances in diagnostic imaging. A conventional standard method involves RI or CT cisternography with a contrast medium injected into cerebrospinal cavity from lumbar vertebra to evaluate malabsorption of spinal fluid into circulation, but diagnosis resulting from use of this method has been reported not to always correlate properly to postoperative prognosis. A relatively new report proposes evaluating a flow of spinal fluid in the aqueduct of midbrain using MRI images (Mase, M. et al., Current Treatment for Hydrocephalus (Tokyo), 8:13-18, 1998). This is an attractive non-invasive method, but is still under development and remains ineffective for some cases. One of the reasons that this method has not come into widespread use is because it can be carried out in only limited facilities.
Among recent successful studies, a report proposes detecting NPH by assessing damage to nerve tissue based on neurofilament triplet protein (NFL) or glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (Tullberg, M. et al., Neurology 60:1122-1127, 1998), but this method has not been made commercial yet.
As described above, surgery is effective for NPH, but there has not yet been developed any detection method for determining whether early surgical treatment of a patient suffering from a demential disease is required.
Prostaglandin D syntheses (PGDSs) include lipocalin type mainly localized in brain and hematopoietic organ type localized in spleen and mast cells, and the PGDS protein found in cerebrospinal fluid has been identified as lipocalin type. Lipocalin-type prostaglandin D synthase (L-PGDS) is an enzyme involved in biosynthesis of prostaglandin D2 in the central nerve system (CNS) of various mammals. This enzyme is mainly produced in cerebral leptomeninges and arachnoid membrane and secreted into cerebrospinal fluid (hereinafter sometimes referred to as CSF). Recently, this L-PGDS has been shown to be identical with β-trace that was known to be present in abundance in CSF (Hoffmann A. et al., J. Neurochem., 61:451-456, 1993; Zahn M. et al., Neurosci. Let., 154:93-95, 1993; Watanabe, K. et al., Biochem. Biophys. Res. Commun., 203:1110-1116, 1994). Studies have been devoted to clinical uses of β-trace in various diseases of the central nerve system because it is a main member of human CSF proteins. However, the involvement or role of PGDS or L-PGDS in various demential diseases remains unexplaind.
An object of the present invention is therefor to provide a method capable of differentiating reliably and with a minimum of stress to a patient normal pressure hydrocephalus that was not detectable or difficult to reliably detect by various conventional test means. Another object of the present invention is to provide a kit for use in the differentiation method.